Development of privileged groebke-blackburn-type 4-(3-aminoimidazo [1,2-α]pyridin-2-yl)benzoic acid core into a combinatorial library on solid phase

Article abstract of DOI:10.2174/157017809789124957

A library of 4-(3-acyl-or carbamoylaminoimidazo[1,2-α]pyridin-2-yl) benzamides (8) was synthesized on solid phase. A suitably protected core acid (1) was synthesized in multigram quantity using previously published procedure and used as the acylating reag

Full text of DOI:10.2174/157017809789124957

Letters in Organic Chemistry, 2009, 6, 491-495
491
Development of Privileged Groebke-Blackburn-Type 4-(3-aminoimidazo
[1,2-a]pyridin-2-yl)benzoic Acid Core into a Combinatorial Library on
Solid Phase
Yuri Sandulenko, Alexander Komarov and Mikhail Krasavin*
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg., 141400, Russia
Received May 19, 2009: Revised August 04, 2009: Accepted August 11, 2009
Abstract: A library of 4-(3-acyl- or carbamoylaminoimidazo[1,2-a]pyridin-2-yl)benzamides (8) was synthesized on solid
phase. A suitably protected core acid (1) was synthesized in multigram quantity using previously published procedure and
used as the acylating reagent for modifying a set of AMEBA resins. Subsequent liberation of the amino group (using a
novel hydrazine procedure) and its acylation or carbamoylation provided, after cleavage, final products in higher chemical
yields and purities compared to known protocols that include formation of the imidazo[1,2-a]pyridine core on solid
support.
Keywords: Imidazo[1,2-a]pyridines, solid phase, combinatorial libraries, isocyanide-based multi-component reactions,
privileged structures.
INTRODUCTION
at the amino group via, for example, acylation (carbamoyl-
ation) [11] or N-arylation [2]. Solid-phase protocols for
production of imidazo[1,2-a]azine libraries via GB-MCR
described to-date, included preparation of resin-supported
aldehyde [11] or isonitrile [12] and exposing such modified
resin to 2-aminoazine and the third reaction partner. Our
initial attempts to produce large (>100 members)
combinatorial arrays using GB-MCR with a resin-supported
reagents resulted in low (<60%) product purities. Therefore,
we decided to explore an alternative strategy by preparing a
suitably functionalized imidazo[1,2-a]azine core in solution
and then using this core as a scaffold for solid-phase
development of the final set of compounds. We recently
reported on the use of tert-butyl isocyanide as a convertible
reagent in GB-MCR. It was shown that removal of the tert-
butyl group from the initially formed tert-butylaminoimidazo
[1,2-a]azines with TFA led to intermediate formation of
trifluoroacetamides (and, hence, the need to hydrolyze them)
[13]. We reasoned that the trifluoroacetyl-protected amino
group of GB-MCR products resulting from such protocol
could be useful as the amino group can be unmasked only
after the imidazo[1,2-a]azine core is placed on solid support
(e. g., via a carboxy function).
The efficient synthesis of imidazo[1,2-x]azines via a
reaction between a 2-aminoazine, an aldehyde and an
isocyanide known as the Groebke-Blackburn multicom-
ponent reaction (GB-MCR) [1], has triggered numerous
efforts to develop combinatorial libraries based on this drug-
like core [2]. This resulted in increased presence of the
respective chemotypes in various screening collections and,
hence, their extensive annotation vs. a number of biological
targets. Analysis of the recent patent literature reveals (Fig.
1) that imidazo[1,2-a]azines manifested themselves as
modulators of sodium channels [3], ubiquitin ligase
inhibitors [4], potential antidiabetic SGLT1 inhibitors [5],
hystone deacetylase inhibitors [6], skeletal muscle myosin
modulators [7], angiogenesis inhibitors [8], as well as
ligands for G-protein coupled receptors (e. g., PAR2 [9]).
Thus, imidazo[1,2-a]azine fragment can be regarded as a
privileged structure for drug design [10]. This consideration
has prompted us to include various Groebke-Blackburn-type
templates in our combinatorial library synthesis program.
Herein, we report on the synthesis of a library of
imidazo[1,2-a]pyridines containing various carboxamide and
urea appendages, on solid phase.
A multigram quantity of the core 4-[3-(trifluoroacetyl-
amino)imidazo[1,2-a]pyridin-2-yl]benzoic acid (1) has been
prepared as described earlier (Scheme 1) [13]. A set of
secondary amine resins 3{1-14} (prepared via reductive
amination [14] of the AMEBA resin [15] with primary
amines 2{1-14} depicted in Fig. 2) was acylated with 1 using
DIC/HOBt method [16]. Removal of trifluoroacetyl group
from 4 with aqueous KOH methanol [13], however, was
found problematic and resulted only in partial conversions,
as monitored by LCMS analysis of the material cleaved off
the solid support. This was unsurprising as the resin was
unlikely to properly swell in aqueous methanol. We found
however, that trifluoroacetyl group is cleanly removed from
4 using hydrazine hydrate in DMF [17]. The primary amino
RESULTS AND DISCUSSION
Besides the use of ring-substituted 2-aminoazines, GR-
MCR products can be diversified i. via the use of various
aldehydes and isocyanides, or ii. by combining a diversity
set of aldehydes with a single convertible isocyanide. In the
latter case, the initially formed GB-MCR products are
converted into primary amines that can be further modified
*Address correspondence to this author at the Chemical Diversity Research
Institute, 2a Rabochaya St., Khimki, Moscow Reg., 141400, Russia; Tel:
+7(495)995-4944; Fax: +7(495)626-9780; E-mail: myk@chemdiv.com
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

492 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Sandulenko et al.
O
O
O
N
H
N
N
S
N
N
N
N
N
O
N
N
N
H
H
H
O
Na+ channel
modulator
Ubuquitin ligase
inhibitor
O
HN
SGLT1 inihibitor
HN
O
O
HO
N
N
N
N
N
H
N
N
N
N
O
N
N
N
N
O
H
N
H
H
N
O
Cl
H
O
OMe
Angiogenesis
inhibitor
OH
PAR2 (GPCR)
inhibitor
Skeletal myosin
modulator
HDAC inhibitor
Fig. (1). Selected biologically active Groebke-Blackburn-type imidazo[1,2-a]azines [3-9].
N
N
N
N
N
N
CF3
v
iv
i - iii
N
N
N
H
O
H
H
N
NH2
OH
OH
O
1
O
O
O
Scheme 1. Large-scale synthesis of the library core reagent 1 [13].
Reagents and conditions. (i) 1 eq. 4-OHCC6H4COOMe, MeCN, reflux, 2 h; (ii) TMSCl (1 eq.), MeCN-DCM, rt, 30 min; (iii) t-BuNC (i – iii,
76%); (iv) aq. KOH (1 eq.), rt, 4 h (93%); (v) TFA, reflux, 3 h (88%).
N
F
NH2
NH2
NH2
NH2
NH2
NH2
N
O
2{6}
2{1}
F
2{2}
2{3}
2{5}
2{4}
NH2
NH2
OEt
NH2
NH2
O
N
NH2
2{7}
2{8}
2{10}
2{9}
O
NH2
O
O
NH2
NH2
Cl
2{11}
2{13}
2{14}
2{12}
Fig. (2). Diversity reagents 2{1-14}.

Development of Privileged Groebke-Blackburn-Type
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
493
O
Cl
O
O
Cl
Cl
Cl
Cl
Cl
6{6}
N
N
O
S
O
O
O
O
6{1}
6{2}
6{5}
6{3}
6{4}
O
Cl
O
Cl
S
O
O
Cl
Cl
Cl
O
Cl
O
O
O
O
6{10}
6{11}
6{8}
6{9}
6{12}
6{7}
Cl
Cl
Cl
Cl
O
O
Cl
O
Cl
Cl
O
O
6{15}
6{14}
6{13}
O
6{18}
O
6{16}
O
6{17}
F
F
F
NCO
NCO
6{19}
NCO
NCO
NCO
O
NCO
6{23}
6{20}
6{21}
6{24}
6{22}
Fig. (3). Diversity reagents 6{1-24}.
O
O
R1NH2
(2{1-14})
O
O
PS
PS
R
NaBH(OAc)3
1% AcOH, DMF-DCM
O
NH
3 {1-14}
1, DIC, HOBt
TEA, DMF
O
O
O
CF3
N
H2N
O
N2H4 x H2O
PS
R
N
HN
O
N
PS
R
DMF
N
N
N
O
O
5{1-14}
O
4{1-14}
DCM/py or
DCM
R
R
N
or
Cl
C
6{1-24}
*TFA
O
O
X
NH
X
NH
O
10% TFA-DCM
N
PS
R
N
H
N
N
R
N
N
O
O
8{1-336}
7{1-336}
X = R2 CO or R2 NHCO
PS = polystyrene
Scheme 2. Library synthesis.

494 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Sandulenko et al.
group was now available for further modification. Fourteen
resin-supported GB-MCR-type amines 5 were reacted with a
set of acyl chlorides and isocyanates 6{1-24} Fig. (3).
Following the cleavage with 10% TFA in DCM and
evaporation of the volatiles, the 336 product mixtures 8 were
analyzed by LCMS [18]. To our delight, the desired product
was detected in all cases: 152 compounds were at least 80%
pure and were not purified further (the rest of compounds
were purified by reverse-phase HPLC). Chemical yields of
these products were in the range 25-68% relative to the
amount of 3 used per one final compound, based on
calculated resin loading (Scheme 2). Selected examples of
the compounds 8 and their chemical yields are presented in
Table 1 [19].
CONCLUSION
In conclusion, we have demonstrated that formation of
imidazo[1,2-a]pyridine core via GB-MCR prior to solid-
phase expansion of the library provided advantages to
alternative protocols where GB-MCR is carried out with a
solid phase supported reagents. The synthesized imidazo
[1.2-a]pyridine-based bis-amides and amide ureas
8
represent novel compounds that are now part of biological
annotation program in our laboratories. Additionally, these
findings can potentially be extended to other imidazo[1,2-
x]azines and –azoles prepared by GB-MCR. Currently we
are investigating the scope of the presented combinatorial
approach. The results of our efforts will be reported in due
course.
Table 1. Selected Compounds 8 Prepared in this Work
Compound
8a
R1
X
MW
LC MS m/z (M+1)
Yield, %
O
*
O
*
476.6
477
49
*
O
*
8b
8c
443.5
378.4
444
379
38
64
N
O
*
*
O
O
O
*
*
8d
8e
446.6
502.6
447
503
67
77
S
F
*
O
*
F
O
*
*
8f
502.0
447.6
503
448
45
54
Cl
NH
O
*
*
8g
NH
O
O
*
8h
8i
490.6
457.5
491
458
63
61
*
N
NH
O
O
O
*
*
NH

Development of Privileged Groebke-Blackburn-Type
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
495
[16]
General procedure for acylation of alkylamino AMEBA resin: To a
solution of the core acid 1 (15 mmol) in DMF (30 mL) were added
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diisopropylcarbodiimide
(DIC,
15
mmol)
and
1-
hydroxybenzotriazole (HOBt, 15 mmol) and the resulting mixture
was stirred for 30 min. Then an aminoalkyl resin 3 (10 mmol) was
added and the mixture was thoroughly shaken for 12 h at room
temperature. The resin was separated by filtration, washed twice
with DMF, methanol, dichloromethane, and methanol, and air-
dried. (Note: we established that the 50% molar excess of the acid
1 was required to achieve maximum degree of resin acylation.
However, the acid 1 can easily be recovered from the filtrate
solution). To cap any non-acylated secondary amine centers on the
resin thus obtained, it was shaken with an excess of 10% solution
of acetic anhydride in DCM for 3 hours, filtered off, washed twice
with DCM, methanol, DCM and methanol, and air-dried.
General procedure for removal of trifluoroacetyl group: the
acylated and acetyl-capped resin 4 was suspended in an excess of a
mixture of hydrazine hydrate and DMF (1:4) and the resulting
mixture was shaken at 80 °C for 72 hours. The resin 4 was
separated by filtration, washed twice with DMF, methanol, DCM,
and methanol, and air-dried to give the resin 5. The full amino
group deprotection was achieved as evidenced by LCMS analysis
of TFA cleavage product off a small amount of 5.
[2]
For the most recent examples of isocyanide-based reactions of 2-
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Umkehrer, M.; Ross, G.; Jäger, N.; Burdack, C.; Kolb, J.; Hu, H.;
Alvim-Gaston, M.; Hulme, C. Tetrahedron Lett., 2007, 48, 2213-
2216. (g) Shaabani, A.; Maleki, A.; Moghimi, R. J.; Soleimani, E.
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M.; Noghani, M. A.; Mirzaei, P. Tetrahedron Lett., 2007, 48, 7263-
7265. (i) Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M.
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General procedure for acylation/carbamoylation of 5 and TFA
cleavage of the final compounds: A 0.5 mmol aliquote of the resin
5 was dispersed in a solution of the respective acyl chloride or
isocyanate 6 (3 mmol) and pyridine (3 mmol) in DCM (20 mL).
The resulting mixture was shaken at room temperature for 18
hours. The resin 7 was separated by filtration, washed twice with
DMF, methanol, DCM, and methanol, and air-dried. It was then
dispersed in 10% solution of TFA in DCM (3 mL) and shaken at
room temperature for 2 hours. The resin was filtered off, washed
with a small amount of methanol. The combined filtrate and
washings were evaporated to dryness to provide crude compound 8.
Characterization data for representative compounds: 8a – off-white
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Klein, M.; Gericke, R.; Beier, N.; Cezanne, B.; Tsaklakidis, C.;
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[8]
Lee, K. C.; Sun, E. T.; Wang, H. U.S. Pat. Appl. Publ. US
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(Chem. Abstr., 2008, 729396).
[19]
1
solid, mp = 184 °C (MeOH, decomp.); H NMR (300 MHz, d6-
[9]
Hembrough, T. A.; Agoston, G. E.; Treston, A. M.; Hanson, A. D.
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DMSO) ꢀ 10.6 (s, 1H), 8.55 (t, J = 5.3 Hz, 1H), 8.29 (d, J = 6.4 Hz,
1H), 8.04 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 7.85 (d, J =
8.5 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.30 (t, J = 6.9 Hz, 1H), 3.53
(m, 1H), 3.43 (t, J = 5.6 Hz, 2H), 3.35 (dd, J = 5.6, 12.5 Hz, 2H),
2.46 (d, J = 7.0 Hz, 2H), 1.70-1.85 (m, 8H), 0.99 – 1.30 (m, 5H),
[10]
[11]
[12]
Blackburn, C.; Guan, B. Tetrahedron Lett., 2000, 41, 1495-1500.
Yang, K.; Lou, B. U.S. Pat. Appl. Publ. US 20040127719 (Chem.
Abstr., 2004, 532969).
1.08 (d, J = 6.2 Hz, 6H); 13C NMR (75 MHz, d6-DMSO) ꢀ 172.9,
165.5, 158.5 (q, JC-F = 36.0 Hz, CF3COO-), 139.8, 134.8, 132.2,
131.9, 130.1, 127.6, 126.8, 124.9, 117.3, 115.8 (q, JC-F = 294.0 Hz,
CF3COO-), 115.0, 114.6, 70.6, 65.2, 42.9, 37.0, 34.5, 32.6, 29.8,
25.8, 25.6, 22.1; HRMS (EI) calcd for C28H36N4O3 (M+) 476.6241,
[13]
[14]
Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Sandulenko, Y.;
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General procedure for reductive amination on AMEBA resin: 4-(4-
formyl-3-methoxyphenoxy)butyryl aminomethyl resin (AMEBA
resin, 5.0 g, 8.35 mmol, 1.67 mmol/g) was dispersed in anhydrous
THF (50 mL) and an amine R1NH2 (2) (41.7 mmol) was added. The
resulting suspension was shaken at room temperature for 2 h.
Sodium triacetoxyborohydride (5.3 g, 25.0 mmol) and acetic acid
(2.4 ml, 41.7 mmol) were added and the resulting mixture was
shaken for an additional 16 h at room temperature. The resin was
separated by filtration, washed twice with THF, MeOH, DCM, and
MeOH and air-dried.
1
found 476.6239. 8d - beige solid, mp = 176-178 °C (MeOH); H
NMR (300 MHz, d6- DMSO) ꢀ 10.8 (s, 1H), 8.34 (d, J = 7.5 Hz,
1H), 8.14 (d, J = 9.6 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.66 (t, J =
7.3 Hz, 1H), 7.44 (d, J = 5.3 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 7.10
(d, J = 3.9 Hz, 1H), 7.05 (dd, J = 3.9, 5.9 Hz, 1H), 4.16 (s, 2H),
3.82 (m, 1H), 1.53 (m, 4H), 0.88 (t, J = 7.7 Hz, 6H); 13C NMR (75
MHz, d6-DMSO) ꢀ 170.4, 165.5, 158.2 (q, JC-F = 36.1 Hz,
CF3COO-), 140.1, 136.0, 135.0, 132.8, 132.1, 129.3, 127.7, 127.0,
126.8, 126.5, 125.3, 124.6, 116.7, 115.8 (q, JC-F = 294.2 Hz,
CF3COO-), 114.9, 114.5, 52.2, 36.3, 26.8, 10.5; HRMS (EI) calcd
for C25H26N4O2S (M+) 446.5756, found 446.5761.
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